Atrophin 1 mutant transcript (ATN1)

The Atrophin 1 (ATN1) mutant transcript is the messenger RNA product of the ATN1 gene containing an abnormally expanded CAG trinucleotide repeat in its coding sequence (UniProt P54259). This expansion leads to the translation of a mutant atrophin-1 protein with an elongated polyglutamine (polyQ) tract, which is the primary driver of dentatorubral-pallidoluysian atrophy (DRPLA), a rare and progressive neurodegenerative disorder (NCBI Gene ID: 1822). The mutant transcript and its protein product are toxic to neurons, particularly in the dentate nucleus and the globus pallidus, leading to symptoms such as ataxia, choreoathetosis, and dementia (PubMed PMID: 24503394). Therapeutic strategies focus on reducing the levels of this pathogenic transcript to prevent the accumulation of toxic protein aggregates. Investigational drugs like VO659, an antisense oligonucleotide (ASO), are designed to target the CAG repeat region to induce RNA degradation or block translation (Vico Therapeutics, 2023). A significant challenge in targeting the ATN1 mutant transcript is achieving allele-specific silencing to preserve the essential biological functions of the wild-type protein while minimizing off-target effects on other CAG-repeat-containing genes.

Other names

Atrophin-1 mRNADRPLA transcriptB37 transcriptNOD transcriptCAG repeat expansion transcript

Antisense oligonucleotide-mediated knockdown of mutant mRNA